Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats

Talampanel {(R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-diox olo[4,5-h][2,3] benzodiazepine} is an orally active noncompetitive antagoni st of the AMPA subtype of glutamate excitatory amino acid receptors. The pu rpose of this study was to determine whether treatment with talampanel woul d protect in a rat model of traumatic brain injury (TBI). Twenty-four hours prior to TBI, a fluid-percussion interface was positioned parasagittally o ver the right cerebral cortex. On the following day, fasted rats were anest hetized with 3% halothane, 70% nitrous oxide, and a balance of oxygen; mech anically ventilated and physiologically regulated; and subjected to right p arieto-occipital parasagittal fluid-percussion injury (1.5-2.0 atm). The ag ent (talampanel, bolus infusion of 4 mg/kg followed by infusion of 4 mg/kg/ h over 72 h) or vehicle was administered i.v. starting at either 30 min or 3 h after trauma. Seven days after TBI, brains were perfusion-fixed, corona l sections at various levels were digitized, and contusion areas were measu red. Treatment with talampanel, when instituted 30 min after trauma, signif icantly reduced total contusion area compared to vehicle-treated rats (0.54 +/- 0.25 vs. 1.79 +/- 0.42 mm(2), respectively). When talampanel treatment was begun at 3 h, the neuroprotective effect of the drug was lost. In addi tion, treatment with talampanel starting at 30 min significantly attenuated neuronal damage in all three subsectors of the hippocampal CAI sector comp ared to vehicle-treated rats (normal-neuron counts, right (ipsilateral) med ial CAI: 80.3 +/- 2.0 [talampanel] vs. 66.3 +/- 2.1 [vehicle] (mean SEM); m iddle CAI: 71.5 +/- 2.0 vs. 60.3 +/- 2.2; lateral CAI: 74.5 +/- 3.0 vs. 63. 0 +/- 3.2, respectively). By contrast, when talampanel treatment was begun at 3 h, normal pyramidal-neuron counts were almost identical in both groups . Our findings document that talampanel therapy instituted 30 min after tra uma significantly reduces histological damage.